Nicotine addiction is a major social and health problem in the world today. Nicotine produces extremely stable changes in the brain that underlie long-lived addictive behavior. The long-term objective of this research is to understand how nicotine produces such long-lasting neural changes in the hippocampus, a brain region involved in the formation of memories and the context-dependent learning of drug-associated behaviors. Such knowledge will likely lead to a better understanding of addiction processes and may aid in developing therapies for preventing the relapse, and thereby promoting smoking cessation. Increasing evidence indicates that addictive drugs such as nicotine produce addictive behavior by causing long- lasting modifications of synapses. The N-methyl-D-aspartate receptor (NMDAR) is critical for such long-lasting modifications of synapses. Our study shows that in vivo exposure to nicotine causes the enhancement of NR2B-containing NMDAR-mediated responses via tyrosine phosphorylation, leading to long-lasting long-term potentiation (LTP; considered to be a cellular substrate of learning and memory) in the hippocampus. The effect of nicotine on NMDAR is mimicked by anti-acetylcholinesterase drugs for Alzheimer's disease and prevented by coadministration of a muscarinic receptor antagonist. These observations suggest not only a common signaling pathway stimulated by cholinergic memory enhancing drugs, but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. We hypothesize that nicotine produces long-lasting neural changes by usurping this signaling pathway. The proposed experiments will test this hypothesis by elucidating the nicotine-induced signaling cascade that leads to NR2B-NMDAR-dependent long-lasting synaptic modifications. The specific aims are to determine the roles of: 1) nicotinic acetylcholine receptors in the proposed pathway, 2) acetylcholine and muscarinic receptors in the nicotine-induced enhancement of NR2B-NMDAR responses; 3) muscarinic receptor-Src tyrosine kinase signaling pathway in the effect of nicotine; and 4) nicotine-induced enhancement of NR2B-NMDAR responses in long-lasting synaptic modifications. The proposed research will be carried out using nicotine- and other drug- exposed animals with a combination of electrophysiological, molecular biological, and morphological approaches. In addition to muscarinic receptor knockout mice, recombinant adenovirus vectors will be used to alter the activity of proteins in the proposed signaling pathway. Results from these studies will not only help determine the cellular basis of nicotine-mediated neuroplasticity, but also aid in developing effective treatments for smoking cessation. Nicotine abuse is one of the major health problems in the world today. Increasing evidence indicates that addictive drugs such as nicotine produce addictive behavior by causing long-lasting neural changes in brain pathways subserving learning and memory. The goal of this project is to determine how nicotine produces such changes in the hippocampus, a brain region involved in context-dependent learning of drug-associated behaviors. Results from this study will likely lead to a better understanding of addiction processes and may aid in developing therapies for preventing the relapse, and thereby promoting smoking cessation.